Implantable Medical Devices Comprising a Flavonoid or Derivative Thereof for Prevention of Restenosis

Abstract

The present invention relates to implantable medical devices, such as stents, that comprise a composition for controlled delivery of flavonoids or a derivative thereof. The flavonoids are aimed at preventing or reducing secondary complications which can occur following implantation of the device such as e.g. occlusive and catastrophic vascular phenomena. The invention further relates to the inclusion of additional therapeutic agents in the system that may have antiproliferative, antimitotic, antimicrobial, anticoagulant, fibrinolytic, anti-inflammatory, immunosurpressive, and anti-angiogenic activities. The composition comprising the flavanoids and optional further therapeutic agents may be used in methods for treating or preventing narrowing or obstruction of the body passageway. In particular the devices and compositions of the invention are useful in methods for treating or preventing restenosis, e.g. subsequent to angioplasty and/or for preventing or reducing acute, subacute and chronic secondary complications associated with angioplasty, such as e.g. thrombus.

1 - 39 . (canceled) 
     
     
         40 . An implantable medical device comprising a composition for controlled release of a flavonoid or a derivative thereof, wherein the flavonoid or derivative thereof is capable of inhibiting tyrosine kinase, DNA topoisomerase-II and/or platelet aggregation, and wherein the composition comprises a further therapeutic agent in addition to the flavonoid or derivative thereof. 
     
     
         41 . A device according to  claim 40 , wherein the flavonoid or derivative thereof is a flavanone, a flavonol, an isoflavone or derivatives thereof. 
     
     
         42 . A device according to  claim 41 , wherein the flavonoid or derivative thereof is selected from genistein, quercetin, rutin, narigenin, naringin and derivatives thereof. 
     
     
         43 . A device according to  claim 41 , wherein the composition for controlled release comprises a soluble polymer. 
     
     
         44 . A device according to  claim 43 , wherein the soluble polymer is a biocompatible or bioresorbable polymer. 
     
     
         45 . A device according to  claim 44 , wherein the bioresorbable polymer is selected from polysaccharides, polyglycolic acid, polylactic acid, polycaprolactone, poly(ethylene terephthalate), poly(butic acid), poly(valeric acid), polyanhydrides, and polyorthoesters and blends and copolymers thereof. 
     
     
         46 . A device according to  claim 40 , wherein the device is a stent, preferably a stent comprising generally tubular structure. 
     
     
         47 . A device according to  claim 46 , wherein the stent is for a body passageway selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system. 
     
     
         48 . A device according to  claim 40 , wherein the further therapeutic agent is selected from antiproliferative, antimitotic, antimicrobial, anticoagulant, fibrinolytic, anti-inflammatory, immunosurpressive, and anti-angiogenic agents. 
     
     
         49 . A device according to  claim 40 , wherein the further therapeutic agent is for preventing or reducing restenosis. 
     
     
         50 . A device according to  claim 40 , wherein the further therapeutic agent is paclitaxel, a derivative of paclintaxel, sirolimus, or a derivative of sirolimus. 
     
     
         51 . A device according to  claim 40 , wherein the device comprises at least two different compositions for controlled release of the flavonoid or derivative thereof and optionally the further therapeutic agent 
     
     
         52 . A device according to  claim 51 , wherein the different compositions are present as subsequent layers at the surface of the device. 
     
     
         53 . A device according to  claim 51 , wherein the different compositions each differ from each other with respect to the concentration of at least one of the further therapeutic agent and the flavonoid or derivative thereof. 
     
     
         54 . A device according to  claim 51 , wherein the different compositions differ from each other with respect to the polymer-composition. 
     
     
         55 . A device according to  claim 51 , wherein the different compositions comprise a first composition comprising the flavonoid or derivative thereof and a second composition comprising paclitaxel or a derivative of paclitaxel and the flavonoid or derivative thereof. 
     
     
         56 . A device according to  claim 51 , wherein the different compostions comprise a first composition comprising the flavonoid or derivative thereof and a second composition comprising sirolimus or a derivative of sirolimus and the flavonoid or derivative thereof. 
     
     
         57 . A device according to  claim 40 , wherein the device comprises an external protective coating, whereby preferably the protective coating comprises no therapeutic agent. 
     
     
         58 . A device according to  claim 57 , wherein the protective coating is polyvinyl pyrolidon. 
     
     
         59 . A method for treating narrowing or obstruction of a body passageway, the method comprising placing a medical device as defined in  claim 40  in the narrowed or obstructed body passageway in a subject in need thereof. 
     
     
         60 . A method according to  claim 59 , wherein the body passageway is selected from arteries, veins, lacrimal ducts, trachea, bronchi, bronchiole, nasal passages, sinuses, eustachian tubes, the external auditory canal, oral cavities, the esophagus, the stomach, the duodenum, the small intestine, the large intestine, biliary tracts, the ureter, the bladder, the urethra, the fallopian tubes, uterus, vagina, the vasdeferens, and the ventricular system. 
     
     
         61 . A method according to  claim 60 , wherein the method is a method for the prevention or treatment of restenosis. 
     
     
         62 . A method according to  claim 61 , wherein the method is method for the prevention or treatment of restenosis subsequent to angioplasty. 
     
     
         63 . A method according to  claim 62 , wherein the method is a method to inhibit neointimal hyperplasia subsequent to angioplasty. 
     
     
         64 . A method according to  claim 60 , wherein the method is a method for the prevention or reduction of acute, subacute and chronic secondary complications associated with angioplasty. 
     
     
         65 . A method according to  claim 64 , wherein the secondary complications include thrombus. 
     
     
         66 . Use of a flavonoid or derivate thereof for the manufacture of a medicament for the prevention or treatment of restenosis, wherein the flavonoid or derivative thereof is capable of inhibiting tyrosine kinase, DNA topoisomerase-II and/or platelet aggregation, and wherein the medicament comprises a further therapeutic agent in addition to the flavonoid or derivative thereof. 
     
     
         67 . A use according to  claim 66 , wherein the flavonoid is a flavanone, a flavonol, an isoflavone or derivatives thereof. 
     
     
         68 . A use according to  claim 67 , wherein the flavonoid or derivative thereof is selected from genistein, quercetin, rutin, narigenin, naringin and derivatives thereof. 
     
     
         69 . A use according to  claim 66 , wherein the medicament is for the prevention or treatment of restenosis subsequent to angioplasty. 
     
     
         70 . A use according to  claim 66 , wherein the medicament is for the inhibition of neointimal hyperplasia subsequent to angioplasty. 
     
     
         71 . A use according to  claim 66 , wherein the medicament is for the prevention of an acute, subacute and chronic secondary complication associated with angioplasty. 
     
     
         72 . A use according to  claim 71 , wherein the secondary complication includes thrombus. 
     
     
         73 . A use according  claim 66 , wherein the medicament comprises a further therapeutic agent. 
     
     
         74 . A use according to  claim 66 , wherein the further therapeutic agent is selected from antiproliferative, antimitotic, antimicrobial, anticoagulant, fibrinolytic, anti-inflammatory, immunosurpressive, and anti-angiogenic agents. 
     
     
         75 . A use according to  claim 66 , wherein the further therapeutic agent is paclitaxel, a derivative of paclitaxel, sirolimus, a derivative or sirolimus, rapamycin, a derivative of rapamycin. 
     
     
         76 . A use according to  claim 66 , wherein the medicament is administered by implanting an implantable medical device comprising a composition for controlled release of a flavonoid or a derivative thereof.